rs1218889799

chr9-132897596-C-Achr9-132897596-C-Gchr9-132897596-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000368.5(TSC1):c.2640G>T(p.Met880Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M880T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000016 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC1 NM_000368.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.29

Genes affected

TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TSC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.22614953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC1	NM_000368.5	c.2640G>T	p.Met880Ile	missense_variant	21/23	ENST00000298552.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC1	ENST00000298552.9	c.2640G>T	p.Met880Ile	missense_variant	21/23	1	NM_000368.5	P4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 122104 Hom.: 0 Cov.: 29 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000215

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000164

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000129 AC: 13 AN: 1009114 Hom.: 0 Cov.: 37 AF XY: 0.0000117 AC XY: 6 AN XY: 511604

Gnomad4 AFR exome AF: 0.0000411

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000147

Gnomad4 OTH exome AF: 0.0000245

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000164 AC: 2 AN: 122170 Hom.: 0 Cov.: 29 AF XY: 0.0000176 AC XY: 1 AN XY: 56818

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000215

Gnomad4 NFE AF: 0.0000164

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000359 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 30, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 07, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC1 protein function. ClinVar contains an entry for this variant (Variation ID: 534449). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 880 of the TSC1 protein (p.Met880Ile). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2024

The p.M880I variant (also known as c.2640G>T), located in coding exon 19 of the TSC1 gene, results from a G to T substitution at nucleotide position 2640. The methionine at codon 880 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.0092	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.32	T;.;T;.;.;T;.;T;.;.;.
Eigen	Benign	0.019
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.76	N;.;N;.;.;N;.;N;.;.;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.13	N;N;N;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.25	T;T;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.13	T;T;T;.;.;.;.;.;.;.;.
Polyphen		0.083	B;.;B;.;.;B;.;B;.;.;.
Vest4		0.47
MutPred		0.26		Loss of disorder (P = 0.05);.;Loss of disorder (P = 0.05);.;.;Loss of disorder (P = 0.05);.;Loss of disorder (P = 0.05);.;.;.;
MVP		0.30
MPC		0.56
ClinPred		0.69	D
GERP RS		5.8
Varity_R		0.31
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1218889799; hg19: chr9-135772983;